title: Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells.
abstract: BACKGROUND
  Cigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation. We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis.
  
  
  METHODS
  We studied changes in mitochondrial morphology and in expression of markers for mitochondrial capacity, damage/biogenesis and fission/fusion in the human bronchial epithelial cell line BEAS-2B upon 6-months from ex-smoking COPD GOLD stage IV patients to age-matched smoking and never-smoking controls.
  
  
  RESULTS
  We observed that long-term CSE exposure induces robust changes in mitochondrial structure, including fragmentation, branching and quantity of cristae. The majority of these changes were persistent upon CSE depletion. Furthermore, long-term CSE exposure significantly increased the expression of specific fission/fusion markers (Fis1, Mfn1, Mfn2, Drp1 and Opa1), oxidative phosphorylation (OXPHOS) proteins (Complex II, III and V), and oxidative stress (Mn-SOD) markers. These changes were accompanied by increased levels of the pro-inflammatory mediators IL-6, IL-8, and IL-1β. Importantly, COPD primary bronchial epithelial cells (PBECs) displayed similar changes in mitochondrial morphology as observed in long-term CSE-exposure BEAS-2B cells. Moreover, expression of specific OXPHOS proteins was higher in PBECs from COPD patients than control smokers, as was the expression of mitochondrial stress marker PINK1.
  
  
  CONCLUSIONS
  The observed mitochondrial changes in COPD epithelium are potentially the consequence of long-term exposure to cigarette smoke, leading to impaired mitochondrial function and may play a role in the pathogenesis of COPD.
authors.affiliation: Department of Pathology and Medical Biology, Laboratory of Allergology and Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. r.f.hoffmann@umcg.nl.
authors.forename: Roland F
authors.initials: RF
authors.lastname: Hoffmann
authors.forename: Sina
authors.initials: S
authors.lastname: Zarrintan
authors.forename: Simone M
authors.initials: SM
authors.lastname: Brandenburg
authors.forename: Arjan
authors.initials: A
authors.lastname: Kol
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.forename: Shabnam
authors.initials: S
authors.lastname: Jafari
authors.forename: Freark
authors.initials: F
authors.lastname: Dijk
authors.forename: Dharamdajal
authors.initials: D
authors.lastname: Kalicharan
authors.forename: Marco
authors.initials: M
authors.lastname: Kelders
authors.forename: Harry R
authors.initials: HR
authors.lastname: Gosker
authors.forename: Nick Ht
authors.initials: NH
authors.lastname: Ten Hacken
authors.forename: Johannes J
authors.initials: JJ
authors.lastname: van der Want
authors.forename: Antoon Jm
authors.initials: AJ
authors.lastname: van Oosterhout
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
mesh_terms: D000328:Adult; D000368:Aged; D001980:Bronchi / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D034281:Dynamins; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure*; D063154:Mitochondrial Dynamics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D000099202:PTEN-Induced Putative Kinase
chemical_list: D016207:Cytokines; D034281:Dynamins; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D013482:Superoxide Dismutase; D000099202:PTEN-Induced Putative Kinase; C476525:FIS1 protein, human; C415198:OPA1 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human